Obsessive-compulsive disorder (OCD) is a heterogeneous disorder with a variety of phenotypic expressions. Delineation of clinically distinct subtypes of the disorder may be valuable in predicting treatment response and resistance. This review focuses on putative clinical determinants, primarily psychiatric comorbidities, associated with treatment resistance in OCD. Therapeutic strategies used in clinically relevant OCD subtypes (eg, tic-related OCD, hoarding subtype, and schizophrenia spectrum-related OCD) with emphasis on antipsychotic augmentation are also addressed.

OCD is a neurodevelopmental disorder characterized by recurrent or persistent unwanted thoughts, images, or impulses (obsessions), and/or repetitive rituals or mental acts (compulsions) that cause substantial distress and functional impairment. OCD is estimated to affect 2% to 3% of the general population and appears to be the fourth most common psychiatric disorder. OCD is frequently comorbid with other psychiatric disorders, such as schizophrenia spectrum disorders, bipolar disorder, major depressive disorder, and anxiety disorders.1 It is thought to be genetically related to Tourette syndrome2 and may share pathophysiological links with the so-called OCD-spectrum disorders, namely body dysmorphic disorder and trichotillomania.3

Serotonin reuptake inhibitors (SRIs) are considered the most effective and well-established treatment for OCD, supporting the role of the serotonergic (5-HT) system in the pathophysiology of the disorder. During the past 2 decades, a number of controlled trials confirmed therapeutic efficacy of the SRI clomipramine and the SSRIs, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, in patients with OCD.

Although meta-analyses of placebo-controlled trials suggest greater efficacy of clomipramine over the SSRIs, the results of head-to-head trials do not support this assumption.4 Moreover, recently published practice guidelines for the treatment of patients with OCD suggest that SSRIs, not clomipramine, be used for first-line treatment because the SSRIs have fewer adverse effects.5 Since the SSRIs each appear to be equally effective, the choice of the particular medication should be determined by the patient's tolerability for adverse effects, his or her previous treatment response, drug-drug interactions, and pharmacogenetic underpinning of response.

Although introduction of SRIs has undoubtedly improved clinical outcome in a substantial proportion of patients with OCD, roughly 40% to 60% do not respond adequately to SRI therapy. Even patients who are considered to be treatment responders (ie, have a 25% to 35% decline in their Yale-Brown Obsessive Compulsive Scale [Y-BOCS] scores6) continue to experience significant impairment from residual symptoms.7,8 Furthermore, as many as 25% of patients fail to reveal any improvement following initial SRI therapy.7,8 Longer trial durations (at least 10 to 12 weeks) and higher dosages are required to determine treatment resistance in OCD compared with major depressive disorder.9

In many recurrent or chronic medical disorders, combination treatment is widely practiced. In fact, with some disorders, combination treatment is the standard of care (eg, triple antiretroviral therapy for AIDS and the multiple medication protocols for cancer, cardiovascular disease, rheumatoid arthritis). In psychiatry, polypharmacy for patients with bipolar disorder or schizophrenia is not unconventional and often confers many benefits. In bipolar disorder, for example, rational polypharmacy allows the clinician to address subtypes of the disorder that respond to specific pharmacological treatment (eg, the positive therapeutic effect of lithium in patients with euphoric, but not dysphoric, mania). This practice also allows for additional positive therapeutic effects by targeting multiple neurobiological systems.

Multimodal therapies are used not only to achieve treatment response and remission but also to prevent treatment resistance. There is emerging recognition that polypharmacy in OCD leads to favorable treatment response as well as the prevention of resistance. Delineation of clinically and pathophysiologically distinct subgroups of OCD patients should facilitate the development of effective polypharmacy.

Tic-related OCD phenotype

Approximately 30% of patients with OCD also have Tourette syndrome or chronic tics.10 Family studies have demonstrated a substantial aggregation of tic disorders not only in OCD probands but also in their first-degree relatives, suggesting that the disorders are etiologically related and might be variant expressions of the same genes.10 Distinctive features of tic-related OCD phenotypes include the presence of sensory phenomena; intrusive violent and sexual images or thoughts; hoarding and counting rituals; tic-like compulsions; and higher comorbidity with trichotillomania, body dysmorphic disorder, bipolar disorder, attention-deficit/ hyperactivity disorder, and substance abuse.11

McDougle and colleagues12 were the first to note that patients with OCD and tics benefited from augmentation of fluvoxamine with the typical anti-psychotic haloperidol (6.2 ± 3.0 mg), whereas patients without tics did not seem to benefit from such a combination. This underscores the role of the dopaminergic system in tic-related OCD. Major drawbacks of the typical antipsychotic-SSRI combination include the occurrence of extrapyramidal syndrome (EPS), prolactin syndrome, and an increased risk of tardive dyskinesia. Atypical antipsychotics, with their preponderance of 5-HT2A over dopamine D2 receptor antagonism, may offer a safer augmentation option. Relatively low dosages of risperidone (mean, 2.3 ± 0.9 mg),12,13 olanzapine (mean, 6.1 ± 2.1 mg),14 and quetiapine (mean, 169 ± 121 mg)15 were augmented to SSRIs in controlled trials of patients with and without tics and treatment-resistant OCD.

None of these studies showed an advantage of add-on atypical antipsychotics over placebo in tic-related versus non-tic-related OCD, presumably because of small sample sizes. However, the meta-analysis of the combined data revealed an overall favorable response to augmentation with atypical antipsychotics in tic-related OCD.16 The number needed to treat in this OCD subpopulation was 2.3 (95% confidence interval [CI], 1.5 to 5.2) compared with 5.9 (95% CI, 0.07 to 0.27) in non-tic- related OCD, indicating a meaningful relative treatment effectiveness of this strategy in tic-related OCD.16

Overall, current evidence supports the use of risperidone or haloperidol for patients with OCD and tics, because these medications have proven efficacy for both Tourette syndrome and refractory OCD.16 Sedation, increased appetite, and weight gain are the most frequently reported adverse effects associated with atypical antipsychotic drug augmentation. Risk of metabolic syndrome and ketoacidosis should be considered akin to that in other patient populations who are treated with atypical antipsychotics.